METABOLIC-ACTIVATION OF N-BUTYRALDOXIME BY RAT-LIVER MICROSOMAL CYTOCHROME-P450 - A REQUIREMENT FOR THE INHIBITION OF ALDEHYDE DEHYDROGENASE

n-Butyraldoxime (n-BO) is known to cause a disulfiram/ethanol-like rea ction in humans, a manifestation of the inhibition of hepatic aldehyde dehydrogenase (AIDH). As with a number of other in vivo inhibitors of AIDH, n-BO does not inhibit purified AIDH in vitro, suggesting that a metabolite of n-BO is the actual inhibitor of this enzyme. In re-exam ination of the effect of n-BO on blood acetaldehyde levels following e thanol in the Sprague-Dawley rat, we found that pretreatment with subs trates and/or inhibitors of cytochrome P450 blocked the n-BO-induced r ise in blood acetaldehyde in the following order of decreasing potency : 1-benzylimidazole (0.1 mmol/kg) > 3-amino- 1,2,4-triazole (1.0 g/kg) > ethanol (3.0 g/kg) > phenobarbital (0.1% in the drinking water, 7 d ays) > SKF-525A (40 mg/kg). Rat liver microsomes were shown to catalyz e the conversion of n-BO to an active metabolite that inhibited yeast AIDH. This reaction was dependent on NADPH and molecular oxygen and wa s inhibited by CO and 1-benzylimidazole. Hydroxylamine, postulated by others to be a metabolite of n-BO, inhibited AIDH via a catalase-media ted reaction and not through an NADPH-supported microsome-catalyzed re action. Using GLC-mass spectrometry, 1-nitrobutane (an N-oxidation pro duct) and butyronitrile (a dehydration product) were identified as met abolites from microsomal incubations of n-BO. However, neither of thes e metabolic products inhibited AIDH directly or in the presence of liv er microsomes and NADPH. We conclude that another NADPH-dependent, cyt ochrome P450-catalyzed metabolic product of n-BO is responsible for th e inhibition of AIDH by n-BO.